Cleaning Validation - A Risk Based Approach PDF

3/10/2010
Cleaning Validation A Risk Based

Approach
IVT Ireland Conference

March 22-24, 2010
Dublin, Ireland
Agenda
Regulatory Requirements for Cleaning Validation

Quality
Q lit Ri
Risk
kMManagementt G
Guideline
id li R References
f
FDAA REMS Impact
Definition of Cleaning
Risk Management Guidelines and Tools
Risk Approach to Cleaning Validation
Workshop Exercise
Ireland IVT Workshop
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Regulatory Requirements for Cleaning

Validation
USA
FDA 21 CFR Parts 210, 211 (Drugs), 600.11 Biologicals, 820 Medical
Devices Subpart G
FDAs New Guidance -"Process Validation: General Principles and
Practices, November 2008
FDA Inspection Guide, Validation of Cleaning Processes, July 1993
FDA Inspection Guide, Guide to Foreign Medical Device
Manufacturers, September 1995
ASTM E2500 - 07 Standard Guide for Specification, Design, and

Verification of Pharmaceutical and Biopharmaceutical
Manufacturing Systems and Equipment (a precursor to cleaning
validation) http://www.astm.org/Standards/E2500.htm

Validation (Contd) World
Regs.
Active Pharmaceutical Products Committee (APIC) policy

and guidance: Cleaning Validation in API Manufacturing
Plants Policy September 1999; Guidance on Aspects
of Cleaning Validation in Active Pharmaceutical Ingredient
Plants Guidance December 2000
PIC/S: Pharmaceutical Inspection Co-operation Scheme;
July 2004
Recommendations on Validation Master Plan, Installation and
Operational Qualification, Cleaning Validation
Canadian, Cleaning Validation Guidelines Guide-0028
http://www.hc-sc.gc.ca
WHO Supplementary Guidelines on GMP: Validation,
2005
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Validation (Contd)
EU
EC Guide to GMP Part I Annex 15 and Part II

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/pdfs-
en/v4an15.pdf
EC Guide on Risk Assessment Annex 20
European Medicines Agency (EMA)
Directive 2003/94/EC for medicinal products and
investigational
g medicinal p
products for human use ((Article
8)
EudraLex Volume 4 GMP Guidelines (Annex 15)
EMA website: http://www.emea.europa.eu
References Regarding Risk Management

FDA Pharmaceutical cGMPs for the 21st Century, A Risk-
Based Approach, September 2004
ICH Q7A GMP for API November 10, 2000
ICH Q9, Quality Risk Management, November 2005
http://www.ich.org/LOB/media/MEDIA3562.pdf
ICH Q10: Pharmaceutical Quality System, June 2008
http://www.emea.europa.eu/pdfs/human/ich/21473207en.pdf
ISO 14971:2007 Medical Devices Application of Risk
Management to Medical Devices, 01Mar2007
ISPE Risk-MaPP Baseline Guide
Guidance for Industry Risk Evaluation and Mitigation
Strategies (REMS), September 2009
CBER Guidance on Processing Live Vaccines in Multi-
Product Facilities
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FDA Regulations
1963 GMP 133.4, Equipment shall be maintained in a
clean and orderly manner.
1978 cGMPs (21 CFR 210 & 211) have many subparts
that are relevant to cleaning validation:
Subpart C: Buildings and Facilities

Subpart D: Equipment
Subpart E: Control of Components and Drug Product
Container and Closures
Subpart
S b t F:F Production
P d ti and dPProcess Controls
C t l
Subpart H: Holding and Distribution
Subpart J: Records and Reports
FDA Guide To Inspection and Validation

of Cleaning Processes (July 1993)
FDA expects firms to have written procedures (SOP's)
detailing the cleaning processes
processes direct quotation
Emphasis on having different cleaning SOP between
batches of different product
Defines expectation that FDA expects written cleaning validation
process policy
Documented cleaning processes - protocols
Appropriate equipment design
Analytical methods suitable to detect residues or contaminants
Sampling Direct and Rinse
Monitoring
Residue limits (rationale that is practical, achievable & verifiable)
Other issues e.g.; placebo product, detergent and test until clean
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European Regulations and ICH Q7A

4. Buildings and Facilities
4.1 Design and Construction to facilitate cleaning, maintenance and
operations
4.2 All utilities shall be qualified
4.3 Water suitable for use of manufactured product
4.7 Buildings properly maintained and kept in clean condition
5. Process Equipment
5.1 Equipment Design cleanable not additive or absorptive
5.2 Equipment Maintenance and Cleaning
5.20 Schedules and procedures
5.21 Written cleaning procedures
5.22 Equipment and utensils
5.23 Campaign production
5.24 Non-dedicated equipment
5.25 Acceptance criteria for residues
5.26 Equipment identification
12.7 Cleaning Validation

FDA Observations on Cleaning Validation

483 Citations
Written procedures are not established for the cleaning
and maintenance of equipment,
q p including
g utensils, used
in the manufacture, processing packing or holding of a
drug product. Specifically, your firm has not validated
the cleaning procedures for the product contact, multi-
use mixing rods used during formulation of product bulk
solutions. There was no evidence to support that the
mixing rods are dedicated to specific products. There
were no p procedures,, employee
p y training g records,, or
identification showing control and dedication of an
unspecified number of multi-use formulation mixing
rods GMP Trends (August 2008)
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More 483 FDA Observations

Cleaning procedures are non specific on the detergent
quantity to be used and cleaning time for manufacturing
equipment
The
The cleaning validation design did not consider possible
cross-contamination for non-dedicated equipment
No time frames/limitations have been established for
production equipment from end of use to start of
cleaning. Dirty Hold
No time limit for the length of time allowed between
cleaning and the use of the manufacturing Clean Hold
Procedures for verifying design output meets design
input were incomplete.
incomplete No design verification protocol
that would set out specific parameters to be tested during
verification, the acceptance criteria for those parameters,
or steps to be taken in the event results are obtained that
do not conform to expected criteria.
Another 483 Observation
Equipment used in product of oral solid dosage forms is

not always maintained and/or kept in proper condition for
manufacturing operations and to prevent the
contamination of the products processed in the
equipment. The rubber gasket/ring of the drum inverter
valve were observed to be deteriorated and broken (cut).
This rubber gasket in the drum inverter is a product
contact surface. Neither the firms current preventive
maintenance
i t procedure
d nor th
the operation
ti and d cleaning
l i
procedure for the drum inverter equipment includes an
inspection of the equipment gasket for signs of
deterioration. GMP Trends, October 15, 2009
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FDA Observations (Microbial Contamination)
There is currently no cleaning validation data to support

the one-month expiration for cleaned items and the one
month expiration on sterile items that are routinely
assigned to equipment and goods (2006)
GMP Cleaning Validation does not include the worst case

scenario of allowing the blending tanks to stand not
cleaned for the observed time between a manufactured
b t h off material
batch t i l and
d th
the cleaning
l i performed
f db before
f th
the
initiation of the next blending process (2009)
Warning Letters
Inadequate written procedures for the cleaning and
maintenance of equipment, including utensils, used in the
manufacture,, processing,
p g, packing,
p g, or holding
g of drug
g
products have not been established or followed [21CFR
211.67(b)]. (November 2009)
Records of maintenance, cleaning, and sanitization are
not kept as specified in 21 CFR 211.180 and 211.182
[21 CFR 211.67(c)]. (November 2009)
Your firm failed to validate the sonication cleaning process
to remove a substance affixed to the p porous-coatingg area
of implant products such as hip, shoulder, ankle, and knee
products. In addition, you currently do not monitor the
temperature or time of the sonication cleaning processes
(October 2009)
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More Warning Letters
Your firm failed to perform and document equipment

cleaning validation for the production of Healon D
ophthalmic viscoelastic devices. (September 2009)
The company took NO ACTION to reduce the risk or
create additional control measures after the risk priority
numbers for the changed design fell within an
unacceptable zone for set screws, multiaxial body
assemblies and offset body assemblies. The QA team did
nott prepare a risk
i k managementt reportt andd post-marketing
t k ti
reviews were not conducted or documented annually.
(July 2009)
What is FDAA REMS?

FDAAA = Food and Drug Administration Amendments Act
REMS = Risk Evaluation and Mitigation Strategy
FDAA REMS Title IX, Subtitle A, section 901 created new

section 505-1 of FD&CA which authorizes the FDA to require
persons submitting certain application to submit a proposed Risk
Evaluation and Mitigation Strategy to ensure that the benefits of the
new drug outweigh the risks.
Applicable drug application submission must include a REMS
REMS within 120 days which includes an assessment timetable
Elements to Ensure Safe Use (ETASU)
Package Inserts
Labeling
Communication Plan
Administration Videos, etc.
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List of FDA Approved REMS
Licensed drug and

biological products
that were submitted
with risk mitigation
action plans are
now deemed to
have REMS
Risk Evaluation & Mitigation Strategy

REMS Warning Letters
The flash card omits material information, thereby presenting an
unsubstantiated superiority claim for Tracleer, and omits some of
the most serious and important
p risk information associated with the
use of Tracleer. Thus, the flash card misbrands the drug in violation
of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C.
352(a) and 321(n). Cf. 21 CFR202.1(e)(3)(i); (e)(6)(i) & (e)(6)(ii).
Warning Letter November 2008
Video news releases are false or misleading because they omit and
minimize the risks associated with EMBEDA, fail to present the
limitations to its approved indication, and present misleading
claims. The video news releases therefore misbrand the drug in
violation
i l i off the
h F Federal
d lF Food,
d D
Drug, and dCCosmetici A
Act (A
(Act),
) 21
U.S.C. 352(a) and 321(n). Cf. 21 CFR 202.1(e)(5) & (e)(6)(i).
Warning Letter October 2009
Reference:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryIn
formation/Guidances/UCM184128.pdf
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CLEANING
Definition of Cleaning
The process of removing contaminants

from process equipment and maintaining
the condition of equipment such that the
equipment can be safely used for
subsequent product manufacture
A contaminant is the presence of a minor
ingredient in another chemical or mixture,
often at the trace level.
Emphasis is on CONTROL
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Cleaning Validation
Documented evidence that an approved cleaning

procedure will consistently reduce active
pharmaceutical ingredients (API), process
residues, cleaning agents and microbial residues
from product contact equipment surfaces to
acceptable levels for the processing of drug
products
Reference: FDA; Guide to Inspections

Validation of Cleaning Processes, 1993
Why Clean?
Product integrity
Cross-contamination
Cross contamination
Microbial integrity
Adulteration
Lot integrity (identity, quality, purity,
efficacy and potency)
Equipment reuse
Regulatory issues
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Cleaning Step?
Manufacturing
Last stepp
To protect / reuse equipment
Quality
First step
To protect product to be manufactured
Could be various intermediate steps
Cleaning Effects?
Cleaning has NO effect on previously

manufactured product or intermediate
Cleaning only affects subsequently
manufactured products or intermediates
A different type of process validation
focused on equipment maintenance and
reuse
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Carryover in Cleaning Process

DEFINITION:
Maximum Allowable Carryover
(MACO): is the mathematically calculated
(MACO)
quantity of residue from a previous product
(based upon toxicity/pharmacology, mode of
administration, batch size, shared equipment
surface area plus a safety factor) when carried
over into a different product that CAN represent
potential harm to the patient.
Overall Equation
(0.001)(min.dose act. A) (B.S.) (S.A.)

(max dose Prod
(max.dose Prod.B)(S.S.A.)(S.D.A.)
B)(S S A )(S D A )
For swab sample, where:

B.S. = minimum batch size Prod. B
S.A. = sampled area
S.S.A. = shared surface area
S.D.A. = solvent desorption amount
Use care in units! (g/g or g/mL = ppm)
0.001 = dosage safety factor
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Conservative Assumptions for Swab Analysis
Largest shared surface area

Smallest batch size of subsequent product
Largest daily dose of subsequent product
Smallest pharmacological dose of active
residue
Conservative assumption results in lowest
value for limit
Simplest Rinse Calculation
Sampling small parts by immersing in fixed

volume of solvent
Sampling small parts by flushing with fixed
volume of solvent
S.A. = surface area of part
S.D.A. = volume for extraction
Otherwise Calculation is the same:
(0.001)(min.dose act.A) (B.S.) (S.A.)
(max.dose Prod.B)(S.S.A.)(S.D.A.)
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Cleaning Agent Limits

Use same principles as for finished drugs for limit
in subsequent product
Main difference is no dose
In place of dose/safety factor, use ADI
ADI estimated based on LD50
Same route of administration:
ADI = LD50 X body weight
(conversion factor 105)
Limit (ppm)= ADI of cleaning agent X 106

maximum dose of next product
Containment
Definition:
Containment is a strategy for controlling equipment
utilization to prevent potential cross-contamination
cross contamination by
dedicating equipment to a specific product.
EXAMPLE of Dedicated Facilities & Equipment
21 CFR Section 211.42 (d) states, Operations relating

to the manufacture, processing and packing of penicillin
shall be performed in facilities separate from those used
for other drug products for human use
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Key Aspect
Involves intersection of two products

Product just manufactured - good
cleaning to remove residues to acceptable
level
Product subsequently manufactured -
residue levels based on possible
contamination of next product
Must always evaluate effects on
subsequently produced product
What Must Be Validated?
Critical cleaning must be validated

Cleaning between different products
Focus on product contact surfaces
Applies to drug products and APIs
Not required for non-critical cleaning
Floors, walls, outside of vessels
Some intermediate steps (ICH Q7A)
Others
Significant indirect product contact surfaces
Dedicated equipment
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Quality Risk Management

Guidelines
Cleaning Validation Risk Analysis

What is RISK?
Risk History/Development
y p
How Does RISK Apply?
Quality by Design
Design Space
ICH Guidelines
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RISK ILLUSTRATION
RISK = Probability of Occurrence X Severity of Harm
HAZARD HARM
Cause: Driver Distraction: Failure Mode Effect / Consequence

Listening to music (temporarily loses control) Severity Scale
or cell phone
Risk Management Development History

August 21, 2002
FDA Press Release:
Pharmaceutical cGMPs for the 21st Century; A Risk-
Pharmaceutical
Based Approach
September, 2003
FDA issues final report its 21st Century initiative on the
regulation of pharmaceutical manufacturing
September 2004
FDA started a pilot risk
risk-ranking
ranking model for prioritizing
cGMP inspections of pharmaceutical manufacturing
sites
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Risk Management Development History (Contd)
November 2004
ICH Q
Q9 Quality
Q y Risk Management
g
August 2007
ASTM E-2500 is published, approved and accepted
internationally as a standard guide for commissioning &
qualification
In Development
Revision to ISPE Baseline Guide on Commissioning &
Qualification
ISPE Baseline Guide Risk-MaPP same emphasis as ICH
Q9
FDA Risk Assessment Criteria

September 2004 Risk based method for prioritizing cGMP Inspections
of Pharmaceutical Manufacturing Sites a pilot risk ranking model
FDA Risk Factors

Products Process Facility
Intrinsic Process Control History
sterility product type GMP Violations
prescription or OTC operation type inspection results
Dosage Form
Recall History Contamination Vulnerability Product Volume

frequency product type type of operation
severity operation type
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ISPE RISKMaPP
Risk MaPP = Risk Based Manufacture of Pharmaceutical
Products
ISPE Guideline in Draft aligns g intent of ICH Q9 for
setting health-based cross contamination limits and
cleaning validation limits using a science-based approach
ISPE Risk MaPP Rationale is that health based limits
should be developed by pharmacologists, toxicologists
and as part of clinical trial data for NDA or ANDA
submissions
Emphasis is on distinguishing between what constitutes
a HAZARD and what is termed a RISK. It is a clear
separation of what is reasonable versus unachievable -
zero risk is not scientifically sound
Risk Analysis, Management
ICH Q8 = Pharmaceutical Development

QbD (Quality by Design)
ICH Q9 = Quality Risk Management

QRM (Use of Risk Management Tools)
ICH Q10 = Pharmaceutical Quality System

PQS (Change Control, Vendor Audits and
APR)
ICH Guidance Documents for Minimization of Risk and
Quality Management
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Quality By Design (QbD)

ICH Q8
The aim of pharmaceutical development is to design a
quality product and its manufacturing process to
consistently deliver the intended performance of the
product.
The information and knowledge gained from

pharmaceutical development studies and manufacturing
experience provide scientific understanding to support the
establishment of the design space, specifications and
manufacturing controls.
Quality Risk Management Q9

QRM is a systematic process for the assessment,
control, communication and review of risk to the
quality of the product across the product lifecycle
lifecycle.
Principles include:
Evaluation of the risk to quality based upon
systematic knowledge and ultimately link to
protection of the patient..
The level of effort, formality and documentation of
the QRM process should be proportional to the
level of risk
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Risk Management Process

Initiate
ICH Q9 Quality Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Continuous Process
spanning the entire
Risk Evaluation
unacceptable product lifecycle
Risk Management tools

Risk Communication
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the

Quality Risk Management Process
Risk Review
Review Events
Transition from Current Process to QRM
Risk Assessments and Enhanced Design Reviews
Quality by Design
CPPs,
Design Construction C&Q Process Dev CQAs
Validation
Quality, Cost and Schedule Benefits
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Definition of DESIGN SPACE
Defined in ICH Q10 as:
- The multidimensional combination and

interaction of input variables (e.g.,
material attributes) and process
parameters that have been
demonstrated to provide an assurance
of quality
What is Design Space of Cleaning

Key inputs and data are analyzed and evaluated
Product knowledge
Process knowledge
Regulations
Quality Attributes
Critical Processing Parameters
Consideration should be given to:
Soil type
Process method
method, time
time, solubility
solubility, etc.
etc
Equipment design & configuration
Utility Impact, environmental, heat, pressure, etc.
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Key is Process Knowledge

Critical Process Parameters (CPPs) Critical Quality Attributes (CQAs)
Process Visual Inspection

p
Temperature Analytical Residue
Process Pressure Limits
Process Flow Microbial Limits
Process Time Drainability/Drying/
Cleaning Agent Air Blows
Concentration Clean Equipment
q p
Dirty Equipment Hold Time (CEHT)
Hold Time (DEHT) Conductivity/pH
ICH Q10
Product Quality Systems (PQS)
Contents
Introduction
Pharmaceutical Quality Systems
Design considerations
Product realization from a quality perspective
Continual improvement (Change Control,
CAPA, Documentation change management)
Q
QRM to introduce process
p control
Management responsibility
Continual improvement over product lifecycle
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RISK MANAGEMENT TOOLS
Risk Management Strategies
Most Preferred
Avoid
Substitute
Reduce
Transfer
A
Acceptt
Least Preferred
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Risk Decisions
Making Decisions With Uncertainty
Process Factors
Knowledge Controllable
Experience Uncontrollable
(Chance)
Outcome
Decision Implementation
Good/Bad
Constraints
Information, Economics,
Political Environment, Time
Risk Management Tools

PARTIAL LIST
Failure Mode and Effect Analysis (MIL-STD-1629A)
Hazard Analysis and Critical Control Points (HACCP)
Hazard and Operability (HAZOP)
Cause & Effect Analysis (Fishbone Diagram)
Quality Risk Classification and Filtering
Forced Ranking
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What is FMEA and How Does It Work

FMEA is a systematic method of identifying the effects of
a potential product or process failure and methods to
eliminate or reduce the chance of that failure occurring
Failure Mode: the way by which a failure is observed

Failure Effect: the consequence of the failure mode
Failure Cause: the precipitating event - reason for the failure
Occurrence: a measure of the probability or likelihood that the
cause will occur.
Severity: a measure of the effect of the potential failure
Detection: method by which a failure can be discovered (a measure
of the likelihood that the failure can be detected)
Risk Priority Number: (RPN) the total of occurrence, severity and
detection; used to prioritize the overall risk
FMEA Procedure
Develop a Team Charter objectives, scope, identify

team facilitator/sponsor Key someone with Experience
Select the SME team from QA, Regulatory,
Manufacturing, QC, Validation, Engineering,
Maintenance (as applicable to project)
Establish ground rules eliminate subjectivity
Compile and Review Data Relevant to Project
Use PFDs, P&IDs, Tech Transfer Reports,
Manufacturing
g Records,, Historical Information,, etc.
Establish Calibration Methodology
Develop and obtain consensus on a risk-ranking scale
and risk filtering criteria
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Calibration Tool
Risk Ranking Calibration Table
Severity Ranking S Potential Impact of Failure
Very High 5 Effect of failure could potentially cause patient death
High 4 Effect of failure could potentially cause injury and will certainly create regulatory non-compliance
Moderate 3 Effect of failure could potentially lead to increase in patient dissatisfaction, product complaints and
potential regulatory issues
Low 2 Effect of failure could lead to some patient dissatisfaction but unlikely to generate product complaints
Very Low 1 Failure may not be detected and will not result in direct product quality problems
Occurrence Ranking O Occurrence Frequency Probability

Unavoidable 5 Equal to or greater than one occurrence/day
Highly Likely 4 One or more occurrences/week
Occasional 3 More than one occurrences/year
Unlikely 2 Equal to or less than one occurrence/year
Very Remote Occurrence 1 No more than one occurrence every 2 years
Detection Ranking D Detection Mechanism Effectiveness

U d
Undetectable
bl 5 N iinspection
No i or analytical
l i l method
h d to d
detect quality
li d defect
f
Low Detect-ability 4 Very unlikely that defect will be detected by available PCS, in-process assays or qualitative
inspections
Medium Detect-ability 3 Controls may detect the quality defect
Highly Detectable 2 Existing controls are likely to detect the quality defect
Direct Detection Method 1 Existing control systems, in-process assays or inspections in place that will serve as a direct
detection method for the defect.
FMEA Procedure (Contd)
Risk Identification & Analysis

Select each user requirement and agree on description
& function
Identify all potential failure modes for each function
based on historical information, scientific knowledge
and SME opinion
Then identify all the effects on the process/systems that
could adversely impact product quality in each failure
mode
Next step, determine the severity of each effect, the
probability of occurrence and the potential root causes
Identify the control and detection mechanism in place
for each cause
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Failure Mode and Effect Analysis (FMEA)

Process Risk Assessment
Failure Mode and Effect Analysis (FMEA)
System: Revision:
Subsystem: Revision Date
Designer: Prepare by:

USAGE: Evaluate possible risks relating to product or GMP Impacts (System Approach)
Inputs: Process Flow Diagrams, P&ID, User Requirements Specifications
Definition:
Failure Mode: the way in which the product defect could occur causing the URS to fail
Effect: consequence of a product defect on the patient
Cause of Failure: the likely cause of failure
RPN: Risk Priority Number = severity X probability X detection
Identify, Characterize, Analyze & Evaluate Risk

What might go What are the What is the Current State &
Product/Process wrong? consequences likelihood it Evaluate Risk
User Requirements will go wrong?
Mitigation Actions (hardware, software, analytical, procedural)
Control & Risk
Effect Causes Detection
Failure Mode
URS Description Functions Identify Analyze Determin Indentify Recommended Responsibility Action
item# Potential effect of e the Mechanism Actions & Completion Taken
New Probability
New Detection
Occurrence
Failure failures causes For date
New severity
Detection
New RPN
Modes of failure Controlling
Severity
Cause &
Detecting RPN
Failure
7 Cleaning Contain Chemical Chemical 5 No 3 Leak 15 Install leak Engineering Yes 2 1 1 2

Chemical Chemical overflows exposure overflow detection detector 05Nov09
Storage control system
FMEA Procedure (Contd)

Risk Ranking and Filtering:
Calculate the Risk Priority Number (RPN)
Rank the RPN on some type of risk ranking block diagram
Develop Risk Mitigation Actions
Assign responsibility for each high significant risk to product quality
and track progress
Risk Ranking & Filtering (Severity X Occurrence X Detection)
High Risk Frequency of Occurrence
Severity X Probabiility of Detection
Medium Risk Unavoidable Highly likely Occasional Unlikely Very Remote
Low Risk 5 4 3 2 1
Severity X Probability &

Probability X Severity
5X5&5X5 125 100 75 50 25
5X4&4X5 100 80 60 40 20
5X3&3X5 75 60 45 30 15
5X2&2X5 50 40 30 20 10
5X1&1X5 25 20 15 10 5
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Hazard Analysis and Critical Control

Points (HACCP) Food Industry
1. Conduct a Hazard Analysis
2. Determine the critical control points
3 Establish:
3.
Critical limits
Monitoring procedures
Corrective actions
Verification procedure
Record-keeping and
documentation procedure
Step Hazard Analysis & Evaluation Control & Corrective Actions
No. Description Potential Justification Consequen Severity of Likelihood Hazard to Control Critical Monitoring Corrective
Hazards ce of Exposure of be Measures Limits Procedure Actions
exposure exposure addressed?
to hazard to hazard
5 Canning Enteric Enteric Severe 10 50 Yes Canning to Minimum Check Re-process

pathogens pathogens illness or a specific Temp. of temp. at or dispose
e.g. have been death temperature 124C for completion of canned
Salmonella, or found in 30 of canning food if
P. botulinum poorly minutes inadequate
processed time &
canned foods temp.
Hazard and Operability (HAZOP)
Analysis of operating system, design intent and process variables to ID

consequences, existing controls, risk level and remedial actions
Commonly uses Brainstorming techniques to identify operations that
could results in:
Injury to personnel
Violations of EH&S regulations
Profitability
Ref. Operating Design Process Variable Potential Consequences Existing Risk Remediation
P&ID Intent Deviations Controls Level Actions
(use actions that
could cause
deviations)
PID215 Capping Secure seal Cam pressure, Inadequate pressure Inadequately Visual / Medium Establish procedure
Operation to finished roller pressure or too much sealed vial Physical with instruments to
vial pressure Inspection monitor pressure
range for both process
variables
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Cause and Effect Analysis Process (Fishbone)
1. Draw the fishbone diagram....

2. List the problem/issue to be studied on the "head of the fish".
3 Label each ""bone" of the "fish"
3. "fish". The major categories typically utilized
are:
The 4 Ms:
Methods, Machines, Materials, Manpower
The 4 Ps:
Place, Procedure, People, Policies
The 4 Ss:
Surroundings,g , Suppliers,
pp , Systems,
y , Skills
Start with a Cause and Why for each category as issue
Drill down to root cause using group brainstorming technique
Cause & Effect Analysis (Fishbone Diagram)
Cause
Cleaning
Cleaning
Validation
Validation
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Fault Tree Analysis

Evaluates system or subsystem
failures one at time
Failure analysis flow chart
Failure Mode Assessment Matrix
Event Description Assessment or if probability is known Assignment of Action
Negative Event
Immediate Cause
Immediate Cause
OR AND
contingent
Base human Base
event
cause error Event
event
Quality Risk Classification & Filtering Overview

Risk Likelihood 2 Probability of Detection 3
L M H L M H
O E I O E I
W D G W D G
H H
sification 4
Impact on Quality 1
High High Level 3

Level 3
Medium Medium
Risk Class
Level 2 Level 2
Low Level 1 Low

Level 1
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Complete the Two Risk Tables for API,

EXCIPIENT, Preservatives & Cleaning Agent
API represents greatest patient quality risk 1

Concentration in product means it is likely.
likely
Ability to detect it reliably to low levels is small
Pharmacology can be significant with potent actives
Excipient represents smallest patient risk - 2

Carryover potential high - it constitutes majority of
formula if registered as part of process may
represent very small risk
Visual ability to detect it to safe levels is good
Complete the Two Risk Tables for API,

EXCIPIENT, Preservatives & Cleaning Agent (Contd)
Preservatives are hazardous to patients - 3

Concentration is typically
yp y small
Ability to detect it reliably at low levels is small
Cleaning Agent may be a high patient risk - 4

Carryover should be moderate to low
Ability to detect is high when using those systems
w/in-line p
pH and programmed
p g conductivity
y rinse set
points
Validated analytical and swab methods can lower
carryover concerns at reasonable limits
33
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Example of Forced Ranking - Bioreactor

Sampling Critical Site: Hot Spot Affinity to Role in Cleanability
Location potential (historically MOC or process of Location/
large hard to Surface likely to lead coverage and
contaminant clean) Finish to difficult access
Ranking
area residue
Sidewall 1 1 1 1 1 5
Bottom 5 3 3 1 1 13
Outlet Valve
Dome Lid 1 1 1 1 5 9
Instrument 1 5 3 1 5 15
Port
Sampling 5 5 3 1 1 15
Port
Agitator 1 1 1 1 3 7
OTHER OPTIONS: - Combine Categories (e.g. critical area / hot spot 1 = Low Risk /
- Weight categories (cleanability) 3 = Moderate Risk
- Add Notes Category: like dome ports are hand cleaned, 5 = High Risk / Not
bottom valves are disassemble and cleaned
- Draw equivalence for like ranking (instrument & sample port)
- If ranking locations keep in mid that some of the simple locations may also need to be
assessed to confirm that these locations are in fact clean
Getting Started with the

Risk-Based Approach to
Cleaning
34
3/10/2010
Cleaning Validation Emphasis on

Scientific Adequacy
Documentation, decisions need to demonstrate
cleaning is adequate
Must meet expectations of current in cGMPs
But, NOT a regulatory requirement that each step
be the best choice but must consider RISK and
apply scientific-based rationale
Examples
E l (dirty
(di t h
hold
ld titime, cleaning
l i titime,
swabbing,etc.)
Scale Up Components
Keys in pilot scale/plant evaluation
Confirm lab performance of cleaning agent
Confirm critical control parameters during cleaning
Confirm adequate engineering design & control
Optimize time(s), conditions
Determine rinse conditions
ID sampling locations
Evaluate analytical method and swab method
Define Residue limits for pproducts
Define Analytical Method Capability and Swab
Recovery (Qualify Both)
35
3/10/2010
Documentation For Cleaning Validation Rationale
Lab studies with conclusion

Pilot/scale up studies
Any related studies (toxicology, TOC, clinical
dosage)
Key decisions based on professional judgment
Include why not addressing certain items
Collate as technology transfer or development
report package
Documentation value will be regulatory support as
well as for future review of program
Risk-Based Scientific Rationales Are

Needed For The Following..
- Product grouping or bracketing
- Equipment
E i t grouping
i or bracketing
b k ti
- Residue selection criteria
- Limit selection and calculation
- Analytical approach (direct vs. indirect)
- Sampling method selection
- Sampling site selection criteria
- Campaign and/or minor cleaning strategies
- Disassembly / vessel entry policy
- Monitoring what and when
- Other?
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3/10/2010
How to Start the Assessment Risk Process?
Identify the topic to be addressed

Collect topics or potential arguments for/against the issue
Use brainstorming/process mapping techniques to provide
exhaustive coverage of the cleaning issues
Select proposed RiskMAPP tool to record decisions/data
Gather supporting evidence pro/con for the expected
arguments
Explore all arguments exhaustively pro/con
Record
R d results
lt andd provide
id pertinent
ti t written
itt explanation
l ti
of conclusions Protocol/CVMP
Best Practice for Developing Scientific Rationale

as in FMEA example
Establish a team of interdisciplinary SMEs who have a variety of
perspectives on the issue.
QA / QC
R&D / Technical Operations
Manufacturing / Engineering/Maintenance
Validation
Develop the rationale
Share the rationale in a design review with an independent review
before approval.
Independent reviewer should play inspection / regulatory
advocacy role in an attempt to find weaknesses in the
logic and/or science.
Required attendance and required consensus is an
absolute MUST Remember this is a collaborative effort!
37
3/10/2010
General Quality Risk Management Process
Systematic processes designed to

coordinate,
di t ffacilitate
ilit t andd improve
i
science-based decision making
with respect to risk to quality
An effective quality risk

management system provides a proactive means to identify, control and improve
decision making when a quality problems arises
ICH Fit for Cleaning Validation Risk Analysis

Bridge to Science & Risk Based Methodology
ment
ance
ns
nt
Quality Managem
Risk Assessmen
Product/Process
s
&Report Releasee
Engineering Run
Protocol Accepta
Design Reviews
s
Responsibilities
Residue Levels
Management
Development
Master Plan
Knowledge
Systems
Change
Systems
Roles &
Product Lifecycle
Science & Risk Based Approach

ICH Q8, Q9, Q10 and
FDA GMPs for 21st Century
Regulatory Compliance
38
3/10/2010
WORKSHOP
Group Exercise
NME RiRisk
kSScenario
i
For Existing Cleaning Validation
Out of Clutter, find Simplicity
- Albert Einstein (1879-1955)
Risk Analysis & Cleaning Validation Problem
Situation:
Biopharmaceutical site with an two existing validated products
Product Actives and cleaning agent residual limits established
Products at 4 g/cm2 (4 ppm)
Detergent at 10 g/cm2 (10 ppm)
Cleaning Validation Master Plan closed with most recent product
qualification in validation maintenance state for both products
Problem: New Molecular Entity (NME) being introduced to site

NME calculated to have same active residual limit based upon
pharmacological dose and shared surface area of equipment
Desire is to use the same cleaning cycles for CIP and COP Washer
Systems
39
3/10/2010
Problem additional details
NME requires addition of Dow Corning Antifoam C Emulsion to

bioreactor at a 1:10 dilution (~ 50 mL) each day once the bioreactor
achieves production cell density to eliminate foam in bioreactor
duration of antifoam addition approximately 56 days
No existing analytical test method for Dow Corning Antifoam C
Harvest is concentrated and purified using Protein A
chromatography as first step where ~ 1,000 liters is concentrated
into 40 liters every 2 days
Effect of Dow Corning Antifoam C Emulsion in terms of carryover
on equipment and into the concentrated Protein A chromatography
product stream is unknown no data supplied from R&D as part of
technology transfer See attached MSDS for Dow Corning
Antifoam C Emulsion
Currently using TOC as the method for determination of residual
product and cleaning agent
Resolution Needed
Using a Risk-Based Scientific Approach determine the cleaning

validation path forward for introduction of the new product without
jeopardizing existing product manufacture
Form an SME TEAM with representatives from QA, QC, Validation,
Manufacturing, and any other required department member to
complete a design review and set a strategy for introduction and
validation of the new SME using a risk-based approach
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44

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3/10/2010

Cleaning Validation A Risk Based

IVT Ireland Conference

Regulatory Requirements for Cleaning Validation

Ireland IVT Workshop

Regulatory Requirements for Cleaning

ASTM E2500 - 07 Standard Guide for Specification, Design, and

Regulatory Requirements for Cleaning

Active Pharmaceutical Products Committee (APIC) policy

Regulatory Requirements for Cleaning

EC Guide to GMP Part I Annex 15 and Part II

Ireland IVT Workshop

References Regarding Risk Management

Subpart C: Buildings and Facilities

Ireland IVT Workshop

FDA Guide To Inspection and Validation

European Regulations and ICH Q7A

12.7 Cleaning Validation

FDA Observations on Cleaning Validation

Ireland IVT Workshop

More 483 FDA Observations

Another 483 Observation

Equipment used in product of oral solid dosage forms is

FDA Observations (Microbial Contamination)

There is currently no cleaning validation data to support

GMP Cleaning Validation does not include the worst case

Ireland IVT Workshop

More Warning Letters

Your firm failed to perform and document equipment

Ireland IVT Workshop

What is FDAA REMS?

FDAA REMS Title IX, Subtitle A, section 901 created new

Ireland IVT Workshop

List of FDA Approved REMS

Licensed drug and

Ireland IVT Workshop

Risk Evaluation & Mitigation Strategy

Ireland IVT Workshop

The process of removing contaminants

Documented evidence that an approved cleaning

Reference: FDA; Guide to Inspections

Ireland IVT Workshop

Ireland IVT Workshop

Cleaning has NO effect on previously

Ireland IVT Workshop

Carryover in Cleaning Process

Ireland IVT Workshop

(0.001)(min.dose act. A) (B.S.) (S.A.)

For swab sample, where:

Conservative Assumptions for Swab Analysis

Largest shared surface area

Ireland IVT Workshop

Simplest Rinse Calculation

Sampling small parts by immersing in fixed

Ireland IVT Workshop

Cleaning Agent Limits

Limit (ppm)= ADI of cleaning agent X 106

Ireland IVT Workshop

EXAMPLE of Dedicated Facilities & Equipment

21 CFR Section 211.42 (d) states, Operations relating

Ireland IVT Workshop

Involves intersection of two products

What Must Be Validated?